Abstract The ultimate goal of this project is to understand the underlying factors responsible for in vivo release of parenteral microsphere drug products and to develop a rational mechanism-based approach to create in vitro-in vivo correlations. To summarize this approach-In order to identify potential release mechanisms we propose to (a) determine the characteristic times governing key physical-chemical and/or biological processes that could be rate-limiting to the drug reaching the circulation, (b) the characteristic times identified in (a) will be measured both in vitro and in vivo while monitoring the release (and/or retention) kinetics of model drug-loaded microspheres to elucidate the release mechanism, (c) the in vitro conditions (solution chemistry, mixing, and temperature) will be adjusted between reasonable limits to encompass the rate- controlling characteristic times observed in vivo to identify suitable in vitro conditions for an in vitro-in vivo correlation (IVIVC), and (d) at the same time PK data will be used to confirm direct measurements, to determine if additional rate limits exist (e.g., tissue binding or metabolism) after release from the implant and to establish an IVIVC. The mechanistic evaluation will be conducted using two model drugs a steroid and LHRH agonist. Two formulations for each drug corresponding to two different release mechanisms will be selected for in vitro and in vivo characterization and the development of the IVIVC model. If successful, this proposal has the potential to create a path toward standardization of controlled release assays and rational development of IVIVCs.